1. Field of the Invention
The present invention relates to a process for producing N-(3',4'-dimethoxycinnamoyl)-anthranilic acid, a compound useful as a medicament for treating diseases caused by allergy, and more particularly to a process for producing the compound in a high yield in an industrially advantageous manner.
2. Description of Prior Art
N-(3',4'-dimethoxycinnamoyl)-anthranilic acid can be produced by various methods, including those in which 3',4'-dimethoxycinnamic acid or a derivative thereof is condensed with anthranilic acid or an ester thereof. Among hitherto known methods involving condensation are:
A) A process in which a reactive derivative of 3',4'-dimethoxy-cinnanic is condensed with anthranilic acid (see, e.g., Japanese Patent Publication No. 40,710/81 and Japanese Patent Application (Laid Open) No. 32,756/85); PA0 B) A process in which a reactive derivative of N-(3',4'-dimethoxycinnamoyl)-anthranilic is condensed with an ester of anthranilic acid, followed by the hydrolysis of the ester (see, e.g., Japanese Patent Publication No. 36,905/82); PA0 C) A process in which 3',4'-dimethoxycinnamic acid is condensed with anthranilic acid or an ester thereof in the presence of a condensing agent (see, e.g., Japanese Patent Publication No. 48,545/83); and PA0 D) A method in which 3',4'-dimethoxycinnamic acid is reacted with anthranilic acid in the presence of excess condensing agent to form [2-(3',4'-dimethoxystyryl)-3,1-benzoxazin-4-one] followed by the hydrolysis thereof (see, e.g., Japanese Patent Publication No. 3,995/84).
In processes A and B mentioned above, 3',4'-dimethoxycinnamic acid must be converted into a reactive derivative prior to condensation. The processes therefore require complicated operations. In addition, the processes involve a heating reaction during which by-products are formed through side reactions and decomposition of raw materials, and hence the yield of the desired compound becomes lower. There are even cases where a hardly separable by-product, 2-(3',4'-dimethoxystyryl)-3,1-benzoxazodin-4-one, is formed. In such cases, complicated purification steps are required. Process B, which utilizes an ester of anthranilic acid, is also disadvantageous in that it requires such additional steps as hydrolysis of the ester group and desalination with an acid.
Process C is advantageous in that there is no need for the conversion into a reactive derivative. However, when anthranilic acid is employed as a starting material and a condensing agent is used in around stoichiometric quantity, the desired compound could hardly be obtained because of undesirable side reactions. The process is therefore practiced by using a condensing agent in an amount less than stoichiometrically required, preferably ca. 0.4 times the quantity required stoichiometrically. It is therefore inevitable that the desired product can be produced at a low yield. In addition, by-products are still formed in large quantities including those which could hardly be separated, and hence the process requires complicated purification steps.
Process D was proposed as a method for overcoming such disadvantages. However, it is still unsatisfactory as an industrial process since the desired product could not be produced directly and hence complicated operation is required. In addition, the yield of the desired product is still not high owing to by-products.